Public Assessment Report
Scientific discussion
Ketilept Retard
50 mg, 150 mg, 200 mg, 300 mg and 400 mg
prolonged-release tablets
Quetiapine (as quetiapine fumarate)
DK/H/2326/001-005/DC
21 January 2016
This module reflects the scientific discussion for the approval of Ketilept Retard. The procedure
was finalised on 11 November 2014. For information on changes after this date please refer to the
module ‘Update’.
I.
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing
authorisation for Ketilept Retard 50 mg, 150 mg, 200 mg, 300 mg and 400 mg prolonged-release tablets
from Egis Pharmaceuticals PLC.
The product is indicated for the treatment of schizophrenia and bipolar disorder and as add-on treatment
of major depressive episodes in patients with Major Depressive Disorder (MDD).
A comprehensive description of the indications and posology is given in the SmPC.
Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite,
norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine
exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2- receptors. It is this combination
of receptor antagonism with a higher selectivity for 5HT2 relative to D2- receptors, which is believed
to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability
of quetiapine compared to typical antipsychotics.
This decentralised procedure concerns a generic application claiming essential similarity with the
reference product Seroquel 25 mg, 100 mg and 200 mg film-coated tablets which has been registered in
in Denmark by AstraZeneca A/S since 2001. Seroquel Prolong 50 mg, 150 mg 200 mg, 300 mg and 400
mg prolonged-release tablets have been registered in Denmark by AstraZeneca A/S since 2008 and 2009
(150 mg), respectively.
The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.
II.
II.1
QUALITY ASPECTS
Introduction
Each prolonged-release tablet contains 50 mg, 150 mg, 200 mg, 300 mg or 400 mg quetiapine (as
quetiapine fumarate).
The 50 mg tablets are white to off white, round biconvex tablets, 7.1 mm in diameter and 3.2 mm in
thickness, engraved with “50” on one side.
The 150 mg tablets are white to off white, oblong biconvex tablets, 13.6 mm in length, 6.6 mm in width
and 4.2 mm in thickness, engraved with “150” on one side.
The 200 mg tablets are white to off white, oblong biconvex tablets, 15.2 mm in length, 7.7 mm in width
and 4.8 mm in thickness, engraved with “200” on one side.
The 300 mg tablets are white to off white, oblong biconvex tablets, 18.2 mm in length, 8.2 mm in width
and 5.4 mm in thickness, engraved with “300” on one side.
The 400 mg tablets are white to off white, oval biconvex tablets, 20.7 mm in length, 10.2 mm in width
and 6.3 mm in thickness, engraved with “400” on one side.
The tablets are packed in PVC/PCTFE/Aluminium foil blisters packed into cardboard boxes in packsizes of: 10, 30, 50, 60 and 100 tablets.
However, not all pack sizes may be marketed.
The excipients in the tablet core are: Lactose anhydrous; magnesium stearate; methacrylic acid – ethyl
acrylate copolymer (1:1) type A; crystalline maltose and talc.
The tablet coating contains: Methacrylic acid – ethyl acrylate copolymer (1:1) type A and triethyl citrate.
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The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place
for this product type at all sites responsible for the manufacturing of the active substance as well as for
the manufacturing and assembly of this product prior to granting its national authorisation.
II.2
Drug Substance
The product contains quetiapine fumarate as active substance The active substance is adopted in Ph.
Eur.
INN: Quetiapine fumarate
Chemical name(s):
2-[2-(4-dibenzo [b,f] [1,4] thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol fumarate or
11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo [b,f] [1,4] thiazepine fumarate
Molecular formula: (C21H25N3O2S)2, C4H4O4
Molecular mass: 883.1
Molecular structure:
Quetiapine fumarate is a white to off white powder. It is soluble in dimethylformamide and in glacial
acetic acid, and sparingly soluble in methanol. No chiral centres are observed and consequently no
isomerism is expected. Quetiapine fumarate exhibits polymorphism.
The documentation on the active substance quetiapine fumarate is provided as a Eropean Drug Master
File. The overall specifications are satisfactory and test methods have been presented in adequate detail.
The drug substance specification is in line with the EP monograph for quetiapine fumarate.
An appropriate retest period has been set based on the presented stability studies.
II.3
Medicinal Product
The proposed drug product is a prolonged-release tablet for oral administration containing quetiapine
fumarate in the strengths of 50 mg, 150 mg, 200 mg, 300 mg and 400 mg.
The manufacturing process is a standard process using wet granulation method. The manufacturing
process has been validated and the validation reports are provided.
The tablets are formulated using common excipients described in the European Pharmacopoeia. The
product development has been adequately described.
The manufacturing process has been adequately described and satisfactorily validated on production
batches.
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The tests and acceptance criteria proposed in the product specification are generally considered
appropriate to control the finished product.
Updated stability data up to 24 months on production scale batches and pilot batches have been presented
and the data support an extrapolation of the shelf-life to 3 years with no storage precaution.
III.
III.1
NON-CLINICAL ASPECTS
Introduction
Pharmacodynamic, pharmacokinetic and toxicological properties of quetiapine fumarate are well
known. As quetiapine fumarate is a widely used and well-known active substance, the MAH has not
provided additional studies and none are required. An overview based on a literature review is therefore
appropriate.
The non-clinical overview report refers 23 publications up to year 2013. The non-clinical overview on
the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
III.2
Ecotoxicity/environmental risk assessment (ERA)
Since Ketilept Retard is intended for generic substitution, this will not lead to an increased exposure to
the environment. An environmental risk assessment is therefore not deemed necessary.
IV.
IV.1
CLINICAL ASPECTS
Introduction
Quetiapine fumarate is a well-known active substance with established efficacy and tolerability.
As quetiapine fumarate is a widely used, well-known active substances, the MAH has not provided
additional studies (apart from the bioequivalence studies referenced below) and further studies are not
required. Overview based on literature review is, thus, appropriate.
The clinical overview report refers 35 publications up to year 2013. The clinical overview on the clinical
pharmacology, efficacy and safety is adequate.
IV.2
Pharmacokinetics
To support the application five bioequivalence studies are provided as described below:
200 mg single-dose, fed study
The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way
crossover, single-dose bioavailability study conducted under fed conditions with a wash out period of 7
days between the two administrations. 200 mg of either the test product Ketilept Retard 200 mg
prolonged-release tablets or the reference product Seroquel 200 mg prolonged-release tablets,
AstraZeneca UK Ltd, from the UK market, was administered in each period.
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A two-stage approach was used, according to the EMA guidance CPMP/EWP/QWP/1401/98 Rev.1. An
initial group (Stage 1) of 44 subjects was dosed and their data was analysed. If bioequivalence was not
demonstrated and the power was < 80%, an additional group (Stage 2) was to be enrolled in the study.
If bioequivalence was demonstrated after stage 1, the study would be stopped and no additional subjects
would be dosed.
44 healthy subjects participated in the study. 42 subjects completed the study.
The primary variables for conclusion of bioequivalence were: AUC0-t and Cmax.
The ratio of geometric least square means with corresponding 94.12% confidence interval calculated
from the exponential of the difference between the test and reference product for the ln-transformed
parameters Cmax and AUCt should all be within the 80.00 to 125.00% bioequivalence range in order to
conclude bioequivalence.
Results
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range)
The results from stage 1 show that the 94.12% confidence interval about the test/reference ratio of
geometric means for the AUCt and Cmax parameters were within the acceptance range of 80.00% 125.00%. It was not necessary to move forward with stage 2.
Bioequivalence was demonstrated between Ketilept Retard 200 mg prolonged-release tablets and
Seroquel Prolong 200 mg prolonged-release tablets (AstraZeneca UK Limited) under fed conditions.
200 mg single-dose, fasting study
The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way
crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period
of 7 days between the two administrations. 200 mg of either the test product Ketilept Retard 200 mg
prolonged-release tablets or the reference product Seroquel 200 mg prolonged-release tablets,
AstraZeneca UK Ltd, from the UK market, was administered in each period.
A two-stage approach was used, according to the EMA guidance CPMP/EWP/QWP/1401/98 Rev.1. An
initial group (Stage 1) of 44 subjects was dosed and their data was analysed. If bioequivalence was not
demonstrated and the power was < 80%, an additional group (Stage 2) was to be enrolled in the study.
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If bioequivalence was demonstrated after stage 1, the study would be stopped and no additional subjects
would be dosed.
40 healthy male subjects participated in the study. 40 subjects completed the study.
The primary variables for conclusion of bioequivalence were: AUC0-t and Cmax.
The ratio of geometric least square means with corresponding 94.12% confidence interval calculated
from the exponential of the difference between the Test and Reference product for the ln-transformed
parameters Cmax and AUCt should all be within the 80.00 to 125.00% bioequivalence range in order to
conclude bioequivalence.
Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range)
The results from stage 1 show that the 94.12% confidence interval about the test/reference ratio of
geometric means for the AUCt and Cmax parameters were within the acceptance range of 80.00% 125.00%. It was not necessary to move forward with stage 2.
Bioequivalence was demonstrated between Ketilept Retard 200 mg prolonged-release tablets and
Seroquel Prolong 200 mg prolonged-release tablets (AstraZeneca UK Limited) under fasting conditions.
50 mg single-dose, fasting study
The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way
crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period
of 7 days between the two administrations. 50 mg of either the test product Ketilept Retard 50 mg
prolonged-release tablets or the reference product Seroquel 50 mg prolonged-release tablets,
AstraZeneca UK Ltd, from the UK market, was administered in each period.
A two-stage approach was used, according to the EMA guidance CPMP/EWP/QWP/1401/98 Rev.1. An
initial group (Stage 1) of 44 subjects was dosed and their data was analysed. If bioequivalence was not
demonstrated and the power was < 80%, an additional group (Stage 2) was to be enrolled in the study.
If bioequivalence was demonstrated after stage 1, the study would be stopped and no additional subjects
would be dosed.
40 healthy male/female subjects participated in the study. 38 subjects completed the study. Data from
37 subjects were included in the pharmacokinetic evaluation.
The primary variables for conclusion of bioequivalence were: AUC0-t and Cmax.
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The ratio of geometric least square means with corresponding 94.12% confidence interval calculated
from the exponential of the difference between the test and reference product for the ln-transformed
parameters Cmax and AUCt should all be within the 80.00 to 125.00% bioequivalence range in order to
conclude bioequivalence.
Results
Table 3. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range)
The fasting study with the 50 mg strength does not fulfil the acceptance criteria set up for the two-stage
design regarding Cmax. A decision was taken not to follow the protocol and stage two was not initiated,
because the standard acceptance criteria (90% confidence interval) was fulfilled. This approach is not
applicable for a two-stage study and the study was therefore deemed incomplete, because stage two was
not initiated.
Additional 50 mg, single dose, fasting study
A second additional bioequivalence study with the 50 mg strengths was presented.
The study was a single-dose, randomized, open-label, crossover, pivotal, comparative bioavailability
study of Ketilept Retard 50 mg prolonged-release tablets and Seroquel Prolong 50 mg prolonged-release
tablets (AstraZeneca UK Ltd.) in healthy male and female volunteers under fasting conditions. A
washout period of a minimum of 7 days between each drug administration was applied.
44 healthy male and female subjects participated in the study. 41 subjects completed the study and were
included in the pharmacokinetic evaluation.
The primary variables for conclusion of bioequivalence were: AUC0-t, AUC0-∞ and Cmax.
To establish bioequivalence, the calculated 90% CI for the ratio of geometric means for AUCt and Cmax
for quetiapine should fall within 80.00%-125.00%.
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Results
Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range)
The test/reference ratio of geometric means and the corresponding 90% confidence interval for the AUCt
and Cmax parameters were entirely contained within the acceptance range of 80.00%-125.00%.
The results confirm bioequivalence between the test and reference under fasting conditions.
400 mg steday state study
The study was a steady-state, randomized, open-label, crossover, pivotal, comparative bioavailability
study of Ketilept Retard 400 mg prolonged-release tablets and Seroquel Prolong 400 mg prolongedrelease tablets (AstraZeneca GmbH, Germany) in healthy male and female volunteers under fasting
conditions with up-titration and tapering down (for safety reasons).
48 healthy, male and female subjects participated in the study. 46 subjects completed the study.
The primary variables for conclusion of bioequivalence were: AUCtau, Cmax,ss and Cmin,ss.
Bioequivalence under steady state was to be concluded if the 90% CI for the test/reference ratios of
geometric means for AUCtau, Cmax and Cmin were completely contained within the EMA-defined
acceptance range of 80.00%-125.00%.
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Results
Table 5. Pharmacokinetic parameters in steady-state (non-transformed values; arithmetic mean
± SD) (N = 46)
The results confirm bioequivalence in steady state between the test and reference.
Based on the submitted bioequivalence study Ketilept Retard 400 mg prolonged-release tablets and
Seroquel Prolong 400 mg prolonged-release tablets (AstraZeneca GmbH) are considered bioequivalent
under steady state conditions.
Pharmacokinetic conclusion
The bioequivalence studies confirm bioequivalence between Ketilept Retard 50 mg, 200 mg and 400
mg, prolonged-release tablets and the corresponding strengths of the reference product, Seroquel
Prolong prolonged-release tablets.
The results of the bioequivalence studies can be extrapolated to the 150 mg and 300 mg strengths as
relevant criteria for waiving are fulfilled in accordance with current guidance.
IV.3
Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive
2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to
identify, characterise, prevent or minimise risks relating to Ketilept Retard.
The following safety concerns and proposed risk minimisation measures were agreed upon:
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Table 6. Summary table of safety concerns as approved in RMP
Table 7. Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in
RMP
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V.
USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the requirements
of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing
the PIL was English.
The results show that the package leaflet meets the criteria for readability as set out in the Guideline on
the readability of the label and package leaflet of medicinal products for human use.
The test consisted of: a pilot test followed by two rounds with 10 participants each. The questions
covered the following areas sufficiently: traceability, comprehensibility and applicability.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Ketilept Retard 50 mg, 150 mg, 200 mg, 300 mg and 400 mg prolonged-release tablets has a proven
chemical-pharmaceutical quality and is a generic form of Seroquel Prolong. Seroquel Prolong is a wellknown medicinal product with an established favourable efficacy and safety profile.
Bioequivalence has been shown to be in compliance with the requirements of European guidance
documents.
The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations. A risk management plan describing the pharmacovigilance
activities and interventions designed to identify, characterise, prevent or minimise risks relating to
Ketilept Retard has been presented. An educational program has been set up for healthcare professionals
to help them minimise the occurrence of the following risks:
 Extrapyramidal symptoms
 Somnolence
 Metabolism and nutritional disorders (weight gain)
 Lipid changes (increased cholesterol (including increased LDLs), increased triglycerides, and
 decreased HDLs)
 Hyperglycamia and diabetes mellitus
 Metabolic risk factors
 Potential for off-label use and misdosing.
Agreement between Member States was reached during a written procedure. There was no discussion
in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that
essential similarity has been demonstrated for Ketilept Retard with the reference product, and have
therefore granted a marketing authorisation. The decentralised procedure was finalised on 11 November
2014. Ketilept Retard was authorised in Denmark on 10 March 2015.
According to the List of Union reference dates and frequency of submission of periodic safety update
reports (PSURs), no routine PSURs are required for this product.
The date for the first renewal will be: 11 November 2019.
The following post-approval commitment has been made during the procedure:
- An updated and consolidated version of the ASMF should be submitted before 1 January 2015
including changes implemented in version May 2014 and changes agreed upon during the DCP. If other
changes are included in the updated ASMF, these changes should be applied as variations, preferably as
a type II, B.I.z.
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